Toll-like receptor-9 stimulated plasmacytoid dendritic cell precursors suppress autoimmune neuroinflammation in a murine model of multiple sclerosis

Abstract

Early innate education of hematopoietic progenitors within the bone marrow (BM) stably primes them for either trained immunity or instead immunoregulatory functions. We herein demonstrate that in vivo or in vitro activation within the BM via Toll-like receptor-9 generates a population of plasmacytoid dendritic cell (pDC) precursors (CpG-pre-pDCs) that, unlike pDC precursors isolated from PBS-incubated BM (PBS-pre-pDCs), are endowed with the capacity to halt progression of ongoing experimental autoimmune encephalomyelitis. CpG activation enhances the selective migration of pDC precursors to the inflamed spinal cord, induces their immediate production of TGF-β, and after migration, of enhanced levels of IL-27. CpG-pre-pDC derived TGF-β and IL-27 ensure protection at early and late phases of the disease, respectively. Spinal cords of CpG-pre-pDC-protected recipient mice display enhanced percentages of host-derived pDCs expressing TGF-β as well as an accumulation of IL-10 producing B cells and of CD11c+ CD11b+ dendritic cells. These results reveal that pDC precursors are conferred stable therapeutic properties by early innate activation within the BM. They further extend to the pDC lineage promising perspectives for cell therapy of autoimmune diseases with innate activated hematopoietic precursor cells.

Role of Dendritic Cells in Viral Brain Infections

“…Moreover, a flavonoid, apigenin, was proposed to regulate inflammation by a reduction of a4-chain expression by DC and limiting the BBB cross (174). In the context of MS, there are some studies as the use of prestimulation of DC TLR9 to increase neuroinflammation control and immune regulation of the course of the disease in EAE (175). The use of DC-vaccine was also proposed to support the treatment of neurodegenerative disease as Alzheimer's disease (176).…”

Trained Immunity Contribution to Autoimmune and Inflammatory Disorders

“…Even more interesting is the fact that the transfer of HSCs from FHES-treated mice to naive mice transferred this resistance to developing EAE, showing that the effect was both peripheral and central (99). Besides, in vivo and in vitro stimulation of the TLR-9 in bone marrow induced the migration of precursors of plasmacytoid dendritic cells (pDCs) to the spinal cord and induced the production of TGF-b and IL-27, protecting against the development of EAE (100). On the other hand, at the peripheral level, BCG administration also reduced the severity of EAE in mice by promoting pDCs to induce IL-10-producing Treg cells (101).…”

Toll-Like Receptor Signaling Pathways: Novel Therapeutic Targets for Cerebrovascular Disorders

“…There is growing evidence of the implication of TLRs in various neurodegenerative disorders [ 59 , 60 ], including Alzheimer’s disease [ 61 , 62 , 63 ], Huntington’s disease [ 64 , 65 ], Parkinson’s disease [ 66 ], dementia [ 67 ], and amyotrophic lateral sclerosis [ 68 , 69 ]. Furthermore, TLRs implicated in demyelinating diseases, like multiple sclerosis [ 70 , 71 ] and optic neuritis [ 72 ] and acute neurological disorders, such as epilepsy [ 73 ] and migraine headache [ 74 ], as well as in CNS infections [ 75 ], and traumatic brain injury [ 76 ]. Moreover, TLRs play a role in the modulation of cognitive processes, including learning and memory, and are involved in the pathobiology of psychological disorders, such as anxiety [ 77 ], schizophrenia [ 78 , 79 ], depression [ 80 ].…”